The antigen-specific immune response is a complex biological process that is controlled by multiple layers of positive and negative regulators. T cells are initially stimulated through the T cell receptor (TCR) by the recognition of their cognate peptide antigen presented by major histocompatibility complex (MHC) molecules on antigen-presenting cells. Optimal T cell activation requires a “second signal” provided by costimulatory molecules such as CD28. The immune response is further regulated positively by costimulatory molecules, such as OX40, GITR, and 4-1BB that belong to the TNF receptor super-family, and negatively regulated by checkpoint molecules such as PD-1 and CTLA-4. The function of checkpoint molecules is to prevent undesired overreaction of the immune system in the body; however, they also restrict the ability of the immune system to effectively fight against cancer and infectious disease. Blocking the function of PD-1 or CTLA-4 by an antagonistic monoclonal IgG antibody has been reported to be effective for immunotherapy of cancer in humans (for review, see Pardoll, Nat. Rev. Cancer, 12:252-264, 2012; Mahoney et al., Nat. Rev. Drug Discov. 14:561-584, 2015; Shin et al., Curr. Opin. Immunol. 33:23-35, 2015; Marquez-Rodas et al. Ann. Transl. Med. 3:267, 2015).
Other checkpoint molecules such as TIM-3, LAG-3, TIGIT, BTLA, and VISTA have been reported (Mercier et al., Front. Immunol. 6:418, 2015). TIGIT (T cell immunoreceptor with Ig and ITIM domains), a member of the immunoglobulin superfamily with an immunoreceptor tyrosine-based inhibitory motif (ITIM) in the cytoplasmic tail, is expressed on subsets of activated T cells and natural killer (NK) cells (Yu et al., Nat. Immunol. 10:48-57, 2009). TIGIT is known to interact with CD155 (also called PVR and necl-5), CD112 (also called PVRL2 and nectin-2), and possibly CD113 (also called PVRL3 and nectin-3) (Mercier et al., supra; Martinet et al., Nat. Rev. Immunol. 15:243-254, 2015). Binding of TIGIT with a high affinity ligand CD155, which are expressed on antigen-presenting cells, has been reported to suppress the function of T cells and NK cells (Mercier et al., supra; Joller et al., J. Immunol. 186: 1338-1342, 2011; Stanietsky et al., Eur. J. Immunol. 43:2138-2150, 2013; Li et al., J. Biol. Chem. 289:17647-17657, 2014; Zhang et al. Cancer Immunol. Immunother. Epub on Feb. 3, 2016). TIGIT has also been reported to inhibit T cells indirectly by modulating cytokine production by dendritic cells (Yu et al., supra).
Tumors constitute highly suppressive microenvironments where infiltrating T cells are exhausted and NK cells are silenced by checkpoint molecules such as PD-1 and TIGIT to evade from the immune responses (Johnston et al., Cancer Cell. 26:926-937, 2014; Chauvin et al., J. Clin. Invest. 125:2046-2058, 2015; Inozume et al., J. Invest. Dermatol. Epub on Oct. 12, 2015). A high-level expression of TIGIT on CD8+ T cells has been reported to correlate with poor clinical outcomes of AML subjects (Kong et al., Clin. Cancer Res. Epub on Jan. 13, 2016). The functional defects of exhausted TIGIT+CD8+ T cells from AML subjects were reported to be reversed by the siRNA-mediated knockdown of TIGIT expression (Kong et al., supra). It has also been reported that effector CD8+ T cells during HIV infection in blood and SIV infection in lymphoid tissue exhibit higher levels of TIGIT (Chew et al., PLOS Pathogens, 12:e1005349, 2016). In addition, an ex vivo antibody blockade of TIGIT was reported to restore viral-specific CD8+ T cell effector responses.